CN106045986B - 一种新型吩噻嗪衍生物及其制备方法与应用 - Google Patents
一种新型吩噻嗪衍生物及其制备方法与应用 Download PDFInfo
- Publication number
- CN106045986B CN106045986B CN201610380172.5A CN201610380172A CN106045986B CN 106045986 B CN106045986 B CN 106045986B CN 201610380172 A CN201610380172 A CN 201610380172A CN 106045986 B CN106045986 B CN 106045986B
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- phenothiazine
- reaction
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 125000001484 phenothiazinyl group Chemical class C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 title abstract 2
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 25
- 238000003384 imaging method Methods 0.000 claims abstract description 15
- 108010090849 Amyloid beta-Peptides Proteins 0.000 claims abstract description 12
- 102000013455 Amyloid beta-Peptides Human genes 0.000 claims abstract description 12
- 239000003068 molecular probe Substances 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract 4
- 238000000034 method Methods 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 31
- -1 aldehyde compounds Chemical class 0.000 claims description 24
- 150000002990 phenothiazines Chemical class 0.000 claims description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 238000006482 condensation reaction Methods 0.000 claims description 7
- 238000006000 Knoevenagel condensation reaction Methods 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 claims description 5
- 229950000688 phenothiazine Drugs 0.000 claims description 5
- 229940125782 compound 2 Drugs 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- BGWRYRPOCJXBGX-SNAWJCMRSA-N (E)-3-(10-methylphenothiazin-3-yl)prop-2-enal Chemical compound CN1C2=CC=CC=C2SC=2C=C(C=CC1=2)/C=C/C=O BGWRYRPOCJXBGX-SNAWJCMRSA-N 0.000 claims description 3
- DZCOHLCHTVMOJU-UHFFFAOYSA-N 10-methylphenothiazine-3-carbaldehyde Chemical compound O=CC1=CC=C2N(C)C3=CC=CC=C3SC2=C1 DZCOHLCHTVMOJU-UHFFFAOYSA-N 0.000 claims description 3
- 125000003172 aldehyde group Chemical group 0.000 claims description 3
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 claims description 3
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 2
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 claims 2
- HPKJGHVHQWJOOT-ZJOUEHCJSA-N N-[(2S)-3-cyclohexyl-1-oxo-1-({(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}amino)propan-2-yl]-1H-indole-2-carboxamide Chemical compound C1C(CCCC1)C[C@H](NC(=O)C=1NC2=CC=CC=C2C=1)C(=O)N[C@@H](C[C@H]1C(=O)NCC1)C=O HPKJGHVHQWJOOT-ZJOUEHCJSA-N 0.000 claims 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims 1
- 229910052698 phosphorus Inorganic materials 0.000 claims 1
- 239000011574 phosphorus Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 53
- 230000035945 sensitivity Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000006116 polymerization reaction Methods 0.000 abstract description 2
- 230000006269 (delayed) early viral mRNA transcription Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 41
- 239000007787 solid Substances 0.000 description 41
- 230000015572 biosynthetic process Effects 0.000 description 34
- 238000003786 synthesis reaction Methods 0.000 description 34
- 238000002844 melting Methods 0.000 description 30
- 230000008018 melting Effects 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 23
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- 230000005764 inhibitory process Effects 0.000 description 13
- 230000000694 effects Effects 0.000 description 12
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical class C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 238000004220 aggregation Methods 0.000 description 7
- 125000002820 allylidene group Chemical group [H]C(=[*])C([H])=C([H])[H] 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 238000012544 monitoring process Methods 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 4
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 229940109262 curcumin Drugs 0.000 description 4
- 235000012754 curcumin Nutrition 0.000 description 4
- 239000004148 curcumin Substances 0.000 description 4
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- QDRLGCJQLOXVLY-UHFFFAOYSA-N ethyl 2-(4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl)acetate Chemical compound CCOC(=O)CN1C(=O)CSC1=S QDRLGCJQLOXVLY-UHFFFAOYSA-N 0.000 description 4
- 230000004770 neurodegeneration Effects 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 238000001338 self-assembly Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229940066767 systemic antihistamines phenothiazine derivative Drugs 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 3
- QXBUYALKJGBACG-UHFFFAOYSA-N 10-methylphenothiazine Chemical compound C1=CC=C2N(C)C3=CC=CC=C3SC2=C1 QXBUYALKJGBACG-UHFFFAOYSA-N 0.000 description 3
- XGLVDUUYFKXKPL-UHFFFAOYSA-N 2-(2-methoxyethoxy)-n,n-bis[2-(2-methoxyethoxy)ethyl]ethanamine Chemical compound COCCOCCN(CCOCCOC)CCOCCOC XGLVDUUYFKXKPL-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000000862 absorption spectrum Methods 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 3
- 108010064539 amyloid beta-protein (1-42) Proteins 0.000 description 3
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 238000005238 degreasing Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000013399 early diagnosis Methods 0.000 description 3
- 238000000295 emission spectrum Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 210000002682 neurofibrillary tangle Anatomy 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000002600 positron emission tomography Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000002603 single-photon emission computed tomography Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 238000007039 two-step reaction Methods 0.000 description 3
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 2
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- YXJDAJNCXBSUAB-YPCIICBESA-N (2E,4E)-5-(10-methylphenothiazin-3-yl)penta-2,4-dienal Chemical compound CN1C2=CC=CC=C2SC=2C=C(C=CC1=2)/C=C/C=C/C=O YXJDAJNCXBSUAB-YPCIICBESA-N 0.000 description 2
- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 2
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- KFZGLJSYQXZIGP-UHFFFAOYSA-N 2-chloro-10h-phenothiazine Chemical compound C1=CC=C2NC3=CC(Cl)=CC=C3SC2=C1 KFZGLJSYQXZIGP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010012289 Dementia Diseases 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000007131 anti Alzheimer effect Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000002189 fluorescence spectrum Methods 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000002595 magnetic resonance imaging Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 231100000915 pathological change Toxicity 0.000 description 2
- 230000036285 pathological change Effects 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- DOMTZTVJNZKUNX-UHFFFAOYSA-N tert-butyl 3-aminopropanoate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)CCN DOMTZTVJNZKUNX-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- GSQBIOQCECCMOQ-UHFFFAOYSA-N β-alanine ethyl ester Chemical compound CCOC(=O)CCN GSQBIOQCECCMOQ-UHFFFAOYSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 description 1
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 1
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 0.000 description 1
- VGNCBRNRHXEODV-XXVHXNRLSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-6-dodecoxy-4,7-dihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCC)C1=CC=CC=C1 VGNCBRNRHXEODV-XXVHXNRLSA-N 0.000 description 1
- QRIKOWKZFXHGLT-NSCUHMNNSA-N (E)-3-(8-chloro-10-methylphenothiazin-3-yl)prop-2-enal Chemical compound ClC1=CC=C2SC=3C=C(C=CC=3N(C2=C1)C)/C=C/C=O QRIKOWKZFXHGLT-NSCUHMNNSA-N 0.000 description 1
- FRHRVQQUICVJDG-UHFFFAOYSA-M 1,3-dioxolan-2-ylmethyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)CC1OCCO1 FRHRVQQUICVJDG-UHFFFAOYSA-M 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- JGRMXPSUZIYDRR-UHFFFAOYSA-N 2-(4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl)acetic acid Chemical compound OC(=O)CN1C(=O)CSC1=S JGRMXPSUZIYDRR-UHFFFAOYSA-N 0.000 description 1
- ZNJRONVKWRHYBF-UHFFFAOYSA-N 2-[2-[2-(1-azatricyclo[7.3.1.05,13]trideca-5,7,9(13)-trien-7-yl)ethenyl]-6-methylpyran-4-ylidene]propanedinitrile Chemical compound O1C(C)=CC(=C(C#N)C#N)C=C1C=CC1=CC(CCCN2CCC3)=C2C3=C1 ZNJRONVKWRHYBF-UHFFFAOYSA-N 0.000 description 1
- AMSRWDACZRKLQG-UHFFFAOYSA-N 2-chloro-10-methylphenothiazine Chemical compound C1=C(Cl)C=C2N(C)C3=CC=CC=C3SC2=C1 AMSRWDACZRKLQG-UHFFFAOYSA-N 0.000 description 1
- ACZRLYKCPWDXIY-UHFFFAOYSA-N 2-cyanoprop-2-enoic acid naphthalen-1-amine Chemical class OC(=O)C(=C)C#N.C1=CC=C2C(N)=CC=CC2=C1 ACZRLYKCPWDXIY-UHFFFAOYSA-N 0.000 description 1
- KUZSBKJSGSKPJH-VXGBXAGGSA-N 5-[(9R)-6-[(3R)-3-methylmorpholin-4-yl]-11-oxa-1,3,5-triazatricyclo[7.4.0.02,7]trideca-2,4,6-trien-4-yl]pyrazin-2-amine Chemical compound C[C@@H]1COCCN1c1nc(nc2N3CCOC[C@H]3Cc12)-c1cnc(N)cn1 KUZSBKJSGSKPJH-VXGBXAGGSA-N 0.000 description 1
- LDIOUQIXNSSOGU-UHFFFAOYSA-N 8-(3-pentylamino)-2-methyl-3-(2-chloro-4-methoxyphenyl)-6,7-dihydro-5h-cyclopenta[d]pyrazolo[1,5-a]pyrimidine Chemical compound CC1=NN2C(NC(CC)CC)=C3CCCC3=NC2=C1C1=CC=C(OC)C=C1Cl LDIOUQIXNSSOGU-UHFFFAOYSA-N 0.000 description 1
- CQDNDCJOQNCUGJ-UHFFFAOYSA-N 8-chloro-10-methylphenothiazine-3-carbaldehyde Chemical compound ClC1=CC=C2SC=3C=C(C=CC=3N(C2=C1)C)C=O CQDNDCJOQNCUGJ-UHFFFAOYSA-N 0.000 description 1
- MITGKKFYIJJQGL-UHFFFAOYSA-N 9-(4-chlorobenzoyl)-6-methylsulfonyl-2,3-dihydro-1H-carbazol-4-one Chemical compound ClC1=CC=C(C(=O)N2C3=CC=C(C=C3C=3C(CCCC2=3)=O)S(=O)(=O)C)C=C1 MITGKKFYIJJQGL-UHFFFAOYSA-N 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 102000009091 Amyloidogenic Proteins Human genes 0.000 description 1
- 108010048112 Amyloidogenic Proteins Proteins 0.000 description 1
- 208000024806 Brain atrophy Diseases 0.000 description 1
- UXKCLTPQRBKROC-UHFFFAOYSA-N C(C)(C)C1=C(C(=CC(=C1)C(C)C)C(C)C)C1=CC=CC=C1.[P] Chemical group C(C)(C)C1=C(C(=CC(=C1)C(C)C)C(C)C)C1=CC=CC=C1.[P] UXKCLTPQRBKROC-UHFFFAOYSA-N 0.000 description 1
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 1
- AEBWFUWNFQYBHJ-UHFFFAOYSA-N CN(C1=CC=C2SC=3C=C(C=CC=3N(C2=C1)C)C=O)C Chemical compound CN(C1=CC=C2SC=3C=C(C=CC=3N(C2=C1)C)C=O)C AEBWFUWNFQYBHJ-UHFFFAOYSA-N 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000003941 amyloidogenesis Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000002888 effect on disease Effects 0.000 description 1
- RJCGNNHKSNIUAT-UHFFFAOYSA-N ethyl 3-aminopropanoate;hydron;chloride Chemical compound Cl.CCOC(=O)CCN RJCGNNHKSNIUAT-UHFFFAOYSA-N 0.000 description 1
- 238000000695 excitation spectrum Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000002795 fluorescence method Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 150000004893 oxazines Chemical class 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 230000009822 protein phosphorylation Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 102000013498 tau Proteins Human genes 0.000 description 1
- 108010026424 tau Proteins Proteins 0.000 description 1
- OSWULUXZFOQIRU-UHFFFAOYSA-N tert-butyl 2-aminoacetate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)CN OSWULUXZFOQIRU-UHFFFAOYSA-N 0.000 description 1
- ZJXHVYSDMUKUCA-UHFFFAOYSA-N tert-butyl 3-aminopropanoate Chemical compound CC(C)(C)OC(=O)CCN ZJXHVYSDMUKUCA-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- JADVWWSKYZXRGX-UHFFFAOYSA-M thioflavine T Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1C1=[N+](C)C2=CC=C(C)C=C2S1 JADVWWSKYZXRGX-UHFFFAOYSA-M 0.000 description 1
- 150000003577 thiophenes Chemical class 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom
- C09K2211/1037—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom with sulfur
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Materials Engineering (AREA)
- Biomedical Technology (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种新型吩噻嗪衍生物及其制备方法与应用,生物医药技术领域。本发明具体公开了结构通式I化合物及其药学上适用的盐,可用作近红外荧光分子探针,还提供了该分子探针的制备方法以及它们的应用。本发明荧光分子结构新颖、灵敏度、选择性好、光稳定性好。该分子与Aβ(1‑42)聚集体有很好的亲合力,同时能够很好地抑制β‑淀粉样蛋白的自聚合。因此,它们不仅能应用于Aβ蛋白斑块的成像,而且也能用于治疗阿茨海默症。
Description
技术领域
本发明属于生物医药技术领域,特别涉及一种新型吩噻嗪衍生物及其制备方法与应用。
背景技术
阿尔茨海默氏病(Alzheimer’s disease,AD)是一种恶性神经退行性疾病,病因迄今未明,目前尚无治愈的特效药物或方法。AD的特征在于认知功能例如记忆、思考、理解、计算、语言、学习能力以及判断能力的逐渐降低,当降低到足以影响个人日常生活行为时确诊为痴呆。据统计目前中国患者超过560万,并随着人口老龄化进程呈快速增长的态势。AD不仅严重危害老年人的健康,而且还给患者家属带来沉重的精神负担,为社会带来巨大的健康危机,更对经济造成巨大的影响,因而引起人们的普遍关注。
越来越多的研究表明,早在AD症状出现前10~20年,大脑中的病理改变已经发生。针对AD的病理机制目前主要有3种假说:淀粉样蛋白沉积、神经元纤维缠结(neurofibrillary tangles)以及胆碱能神经元退行性病变。其中“淀粉样级联假说”被人们广泛认可。该假说认为:在AD发生的早期,β-淀粉样蛋白(Aβ,主要是Aβ40和Aβ42)逐渐聚合沉积形成淀粉样斑块,引发tau蛋白磷酸化和神经纤维缠结,最终导致神经元丢失、退化和痴呆。由于AD发病隐蔽性强,病程缓慢,逐渐发展且不可逆,等根据临床症状可以做出诊断时,往往患者基本己处于中晚期,发病后15-25年由于多种并发症而导致死亡。现有的治疗方案只能起到缓解症状,对于疾病均不能取得明显的治疗疗效和改善作用。如果能尽早发现病症,及时治疗,能起到事半功倍的作用。因此研究和开发针对Aβ斑块的诊断试剂,对于在分子水平研究AD的病理生理过程,以及为疾病的早期诊断和治疗提供依据显得尤为迫切。
分子成像技术对患者创伤小,在分子水平上具有高敏感性,很有希望为AD早期诊断和治疗提供有效依据。磁共振成像(MRI)、正电子发射断层成像(PET)、单光子发射计算机断层显像(SPECT)和近红外荧光(NIRF)成像均能够提供AD脑部变化的信息,具有进行人和动物模型的AD诊断潜力。MRI只有在AD患者脑萎缩发生后才能检测的到,而此时脑组织早已发生了病理学改变。目前,应用于AD患者早期诊断的主要是PET和SPECT成像的Aβ探针。但PET/SPECT成像成本高、有放射性危险、采集数据耗时长、核发射正电子半衰期短且同位素可用性狭窄。然而,近红外荧光(NIRF)成像方法具有许多优点:(1)灵敏度高,可实现微弱信号的检测;(2)检测安全,不接触放射性元素;(3)无需耗时,数据采集过程中实时成像;(4)成本适中,无需昂贵的设备和技术高超的人员;(6)NIRF探针具有较深的组织穿透距离且能大大减少活体组织及自发发光对成像的干扰。近年来近红外荧光(NIRF)成像技术的发展相当迅速,大大加快了对AD研究的步伐。迄今为止,已有一些关于检测Aβ斑块的近红外荧光探针的报道,如噁嗪类衍生物(AOI987),噻吩类衍生物(NIAD),姜黄素类衍生物(CRANAD),硼二吡咯亚甲基类衍生物(BODIPY),氨基萘-2-氰基丙烯酸酯类衍生物(ANCA),共轭π电子链类(DANIRs)。但目前,用于阿尔茨海默氏病淀粉样蛋白β斑块近红外荧光(NIRF)成像探针仍处于临床前研究阶段。
发明内容
为克服上述现有技术中存在的缺点与不足,本发明的首要目的在于提供一种吩噻嗪衍生物。所述的吩噻嗪衍生物可用于阿尔茨海默氏病淀粉样蛋白β斑块成像的新型近红外荧光分子探针,同时能对β-样淀粉蛋白聚合具有抑制作用,而用于治疗阿茨海默症。
本发明的另一目的在于提供上述吩噻嗪衍生物的制备方法。
本发明的再一目的在于提供上述吩噻嗪衍生物的应用。本发明的吩噻嗪衍生物不仅可作为近红外荧光分子探针用于阿尔茨海默氏病淀粉样蛋白β斑块成像,还可应用于该病的治疗。
本发明的目的通过下述技术方案实现:一种吩噻嗪衍生物,具有如式Ⅰ所示通式:
其中:R1为H、Cl或N(CH3)2中的一种;
R2为H、N(CH3)2、Et或tBu中的一种;
R3为CH3;
m为整数1或2;
n为整数1,2或3。
所述的吩噻嗪衍生物,包括由上述式Ⅰ的吩噻嗪衍生物在醇溶液中与盐酸、醋酸、三氟乙酸制备相应的盐酸盐、醋酸盐、三氟乙酸盐。
上述的吩噻嗪衍生物的制备方法,包括如下步骤:
(1)中间体醛化合物2,3,4的制备:吩噻嗪或2-氯吩噻嗪甲基化之后,经维尔斯迈尔-哈克反应引入醛基,得到化合物2,再经磷叶立德反应引入一个烯烃键,得到化合物3,重复同样的反应再引入一个烯烃键,最后得到化合物4;
(2)中间体5的制备:甘氨酸乙酯,叔丁酯盐酸盐或3-氨基丙酸乙酯,叔丁酯与2,2'–(硫代羰基(硫))二乙酸进行缩合反应,得到中间体5;
(3)化合物6,7,8,9,10的制备:10-甲基-10H-吩噻嗪-3-甲醛的8位取代的化合物2与中间体5进行Knoevenagel缩合反应,得到化合物6和9;在酸性条件下脱酯反应,化合物6和9转化成酸7和10;在卡特缩合剂存在条件下,化合物7与二甲胺反应形成酰胺8,其中R1,R2,R3,m,n与权利要求1中相同;
(4)化合物11,12,13,14的制备:参照步骤(3)中有关的反应,(E)-3-(10-甲基-10H-吩噻嗪-3-基)丙烯醛的8位取代的化合物3与中间体5进行Knoevenagel缩合反应,得到化合物11和13;在酸性条件下脱酯反应,化合物11和13转化成酸12和14,其中R1,R2,R3,m,n与权利要求1中相同;
(5)化合物15,16,17,18的制备:同样参照(3)中有关的反应,(2E,4E)-5-(10-甲基-10H-吩噻嗪-3-基)戊-2,4-二烯醛的化合物4与中间体5进行Knoevenagel缩合反应,得到化合物15和17;在酸性条件下脱酯反应,化合物15和17转化成酸16和18,其中R1,R2,R3,m,n与权利要求1中相同;
上述产物的化合物6-18任意一项皆为目标产物吩噻嗪衍生物。
所述步骤(1)的中间体醛化合物2,3,4的制备,具体步骤如下:从商品化的吩噻嗪,2-氯吩噻嗪出发,与碘甲烷在氢化钠碱性条件作用下生成10-甲基吩噻嗪(1a)、2-氯-10-甲基吩噻嗪(1b),反应溶剂采用N,N-二甲基甲酰胺,在室温反应2小时,生成白色固体产物;化合物1b与二甲胺在三(二亚苄基丙酮)二钯的催化下,通常用2-二环己基磷-2,4,6-三异丙基联苯做配体,碳酸铯作为碱,二氧六环作为溶剂,在氩气保护下120摄氏度反应7h后提纯可得到化合物1c;在氩气保护下,化合物1(1a,1b,1c)与三氯氧磷和干燥的N,N-二甲基甲酰胺反应回流10个小时,即得接上一个醛基的黄色产物2(2a,2b和2c);反应溶剂选用N,N-二甲基甲酰胺,二氯甲烷或氯仿,所得产物可经柱层析或重结晶提纯;以三(3,6-二氧杂庚基)胺为相转移催化剂,碳酸氢钠/碳酸钠饱和溶液体系为碱性介质,以二氯甲烷为反应溶剂,化合物2a和2b与(1,3-二氧戊环-2-基)甲基三苯基溴化瞵回流反应20h,经柱层析或重结晶提纯后,得到橘黄色产物3a和3b;之后用上述同样的反应方法化合物3a可以转化成橘黄色产物4a,反应化学方程式如式Ⅱ所示:
所述步骤(2)的中间体5的制备,具体步骤如下:2-(4-氧代-2-硫代噻唑烷-3-基)乙酸或丙酸酯中间体5的制备:从商品化甘氨酸乙酯,叔丁酯盐酸盐或3-氨基丙酸乙酯,叔丁酯盐酸盐出发,以三乙胺作为碱,与2,2'–(硫代羰基(硫))二乙酸盐酸盐发生缩合反应,之后通过柱层析法提纯,即可得到白色固体化合物5,该缩合反应选用异丙醇作为反应试剂,在82℃下回流1h,反应化学方程式如式Ⅲ所示:
所述步骤(3)的化合物6,7,8,9,10的制备,具体步骤如下:从化合物3a,3b和3c出发,以二氯甲烷为溶剂,与中间体5(5a1,5a2,5b1,5b2)进行Knoevenagel缩合反应;在常温下反应2-5h,通过柱层析法提纯,得到化合物6(6a1,6a2,6b1,6b2,6c2)之后,在三氟乙酸酸性条件下,化合物6(6a2,6b2和6c2)进行脱脂反应,形成酸7(7a,7b,7c),重结晶后呈红色固体;采用上述同样的二步反应方法,化合物3a和3b可以转化成化合物9(9a1,9a2)和10;在卡特缩合剂(BOP)存在下,化合物7a与二甲胺进行缩合反应,经适当方法如柱层析、重结晶提纯,可得到化合物8a,反应化学方程式如式Ⅳ所示:
所述步骤(4)的化合物11,12,13,14的制备,具体步骤如下:从化合物3a和3b出发,参照步骤(3)中的二步反应方法,与化合物5(5a1,5a2,5b1,5b2)的缩合反应和脱脂反应,可得到红色固体的目的化合物11,12,13,14,反应化学方程式如式Ⅴ所示:
所述步骤(5)的化合物15,16,17,18的制备,具体步骤如下:从化合物4a出发,参照步骤(3)二步反应方法,与化合物5(5a1,5a2,5b1,5b2)的缩合反应和脱脂反应,可得到红色固体的目的化合物15,16,17,18,反应化学方程式如式Ⅴ所示:
上述的吩噻嗪衍生物的应用,主要体现在,应用于阿尔茨海默氏病淀粉样蛋白β斑块成像的近红外荧光分子探针。
上述的吩噻嗪衍生物的应用,主要体现在,应用制备治疗阿茨海默症的药物。
本发明相对于现有技术具有如下的优点及效果:
1.本发明获得的吩噻嗪衍生物最大吸收和荧光发射光谱值分别在470~510nm和640~700nm之间。大部分的化合物的发射光谱值>650nm;适合用于阿尔茨海默氏病淀粉样蛋白β斑块成像的近红外荧光分子探针的特性。
2.从本发明获得的吩噻嗪衍生物与Aβ(1-42)自聚体的结合能力测试结果来看,这类化合物具有很强的于Aβ自聚体结合能力;另外,在体外化合物与β-淀粉样蛋白的自聚集抑制活性测试中显示,这类化合物对Aβ1-42的自聚集具有较好的抑制作用,它们的抑制作用都比对照物姜黄素要强,最高达到了84.9%抑制强度,而同等条件下,姜黄素的抑制强度仅为41%。因此,这类化合物也具有治疗抗阿茨海默症的潜力。
具体实施方式
下面结合实施例对本发明作进一步详细的描述,但本发明的实施方式不限于此。
实施例1:合成10-甲基-10H-吩噻嗪-3-甲醛2a
称取NaH(60%纯度,1.0g,25.1mmol)在冰水浴中缓慢加入有DMF(10mL)的50mL圆底瓶中,随后加入碘甲烷(1.3g,11.04mmol)和化合物吩噻嗪(2g,10.0mmol),转移至室温搅拌2h,TLC监测反应结束后,加水,用DCM萃取(50mL x 3),硫酸镁干燥后再浓缩干,经硅胶柱分离得到产物1a(2.1g),白色固体,熔点:96℃,收率97%。
1H NMR(400MHz,(CD3)2CO)δ7.21(td,J=8.0,1.5Hz,2H),7.21(d,J=2.0Hz,1H),7.14(d,J=1.5Hz,1H),6.96-6.93(m,4H),3.39(s,3H).
在0℃的冰水浴中,将三氯氧磷(1.98g,1.18mL,12.9mmol)缓慢滴加在有干燥DMF(904L,11.73mmol)的25mL圆底瓶中,搅拌0.5h后,加入溶在5mL DCM的化合物1a(500mg,2.34mmol),将反应体系升温至回流7h。TLC监测反应结束后,加水,用DCM萃取(50mL x 3),硫酸镁干燥后再浓缩干,经硅胶柱分离得到产物2a(320mg),黄色固体,熔点:106℃,收率58%。
1H NMR(400MHz,CDCl3)δ9.78(s,1H),7.64(dd,J=8.7,2.0Hz,1H),7.59(d,J=2.0Hz,1H),7.17(td,J=7.8,1.6Hz,1H),7.11(dd,J=7.8,1.6Hz,1H),6.97(t,J=7.5Hz,1H),6.85(d,J=7.5Hz,1H),6.82(d,J=7.5Hz,1H),3.41(s,3H).
实施例2:合成8-氯-10-甲基-10H-吩噻嗪-3-甲醛2b
参照实施例1第一步操作过程,分离得产物1b,白色固体,熔点:75℃,收率97%;
1H NMR(400MHz,CDCl3)δ7.16(td,J=7.8,1.3Hz,1H),7.12(dd,J=7.8,1.3Hz,1H),6.99(d,J=8.5Hz,1H),6.94(t,J=7.5Hz,1H),6.88(dd,J=8.5,2.0Hz,1H),6.78(d,J=8.5Hz,1H),6.73(d,J=2.0Hz,1H),3.29(s,3H).
参照实施例1第二步操作过程,分离得产物2b,黄色固体,熔点:160℃,收率38%。
1H NMR(400MHz,CDCl3)δ7.16(td,J=7.8,1.4Hz,1H),7.11(dd,J=7.8,1.4Hz,1H),7.01(d,J=8.2Hz,1H),6.93(td,J=7.6,1.4Hz,1H),6.88(dd,J=8.2,2.0Hz,1H),6.8(d,J=8.2Hz,1H),6.75(d,J=2.0Hz,1H),3.35(s,3H).
实施例3:合成8-(二甲基氨基)-10-甲基-10H-吩噻嗪-3-甲醛2c
将二甲胺(1.6mL,3.1mmol,1.5eq)加入溶有化合物1b(500mg,2.02mmol,1eq)的二氧六环(4mL)中,随后加入催化剂三(二亚苄基丙酮)二钯(75mg,0.08mmol,0.04eq)和配体2-二环己基磷-2,4,6-三异丙基联苯(78mg,0.16eq,0.08eq)以及碳酸铯(1.4g,2eq),在氩气保护下120摄氏度反应7h。TLC监测反应结束后,待冷却至室温后先进行抽滤,得到的滤液浓缩干后,采用柱层析法分离得到产物1c(260mg),白色液体,收率50%。
1H NMR(400MHz,CDCl3)δ7.16-7.10(m,2H),6.97(d,J=8.5,1H),6.89(td,J=8.0,1.0Hz,1H),6.8(dd,J=8.0,1.0Hz,1H),6.33(dd,J=8.0,2.5Hz,1H),6.21(d,J=2.5,1H),3.36(s,3H),2.92(s,6H).
化合物1c(227mg,0.89mmol),参照实施例1第二步操作过程,分离得产物2c,黄色固体,熔点:121℃,收率42%。
1H NMR(400MHz,CDCl3)δ9.97(s,1H),7.49(s,1H),7.15(td,J=8.0,1.5Hz,1H),7.12(dd,J=8.0,1.5Hz,1H),6.95(td,J=7.5,1.0Hz,1H),6.82(d,J=7.5Hz,1H),6.32(s,1H),3.42(s,3H),2.91(s,6H).
实施例4:合成(E)-3-(10-甲基-10H-吩噻嗪-3-基)丙烯醛3a
将饱和的碳酸钾溶液(15mL)加入到溶有三(3,6-二氧杂庚基)胺(TDA-1)(738mg,2.28mmol,1.1eq)的DCM(10mL)中,然后按顺序加入(1,3-二氧戊环-2-基)甲基三苯基溴化膦(1.43g,3.32mmol,1.6eq)和化合物2a(500mg,2.07mmol,1eq)。反应体系升温至回流状态搅拌约20h,TLC监测反应结束后,先用(DCM 2x 25mL)萃取,先再用食盐水清洗,有机相用硫酸镁干燥后浓缩干,在0摄氏度下加入20mL的THF和10%的HCl(20mL),室温搅拌1h。将反应体系在0摄氏度冰水浴中用10%的NaOH调节pH至7,再用DCM(2x 25mL)和水萃取,最后用饱和食盐水和硫酸镁干燥后浓缩干,经硅胶柱分离得到产物3a(490mg),橘黄色固体,熔点:129℃,收率是88.6%。
1H NMR(400MHz,CDCl3)δ9.61(d,J=8.0Hz,1H),7.65-7.29(m,3H),7.17(td,J=7.5,1.0Hz,1H),7.12(dd,J=7.5,1.0Hz,1H),6.95(td,J=7.5,1Hz,1H),6.82(d,J=8.5Hz,1H),6.72(d,J=8.5Hz,1H),6.56(q,J=7.8Hz,1H),3.38(s,3H).
实施例5:合成(E)-3-(8-氯-10-甲基-10H-吩噻嗪-3-基)丙烯醛3b
化合物2b(500mg,1.81mmol),参照实施例4操作过程,分离得产物3b(502mg),橘黄色固体,熔点:145℃,收率91%。
1H NMR(400MHz,CDCl3)δ9.62(d,J=7.5Hz,1H),7.36-7.29(m,3H),7.01(d,J=8.0Hz,1H),6.93(dd,J=8.0,2.0Hz,1H),6.8(d,J=8.5Hz,1H),6.78(d,J=2.0Hz,1H),6.57(q,J=7.8Hz,1H),3.39(s,3H).
实施例6:合成(2E,4E)-5-(10-甲基-10H-吩噻嗪-3-基)戊-2,4-二烯醛4a
化合物3b(770mg,2.89mmol),参照实施例4操作过程,分离得产物4a(346mg),橘黄色固体,熔点:138℃,收率62%。
1H NMR(400MHz,CDCl3)δ9.57(d,J=8.0Hz,1H),7.28-7.25(m,2H),7.17(td,J=8.0,1.5Hz,1H),7.12(dd,J=8.0,1.5Hz,1H),6.94(td,J=8.0,1.5Hz,1H),6.89-6.85(m,2H),6.81(d,J=8.0Hz,1H),6.76(d,J=8.0Hz,1H),6.21(q,J=7.5Hz,1H),3.37(s,3H).
实施例7:合成2-(4-氧代-2-硫代噻唑烷-3-基)乙酸乙酯5a1
将甘氨酸乙酯盐酸盐(500mg,3.6mmol,1eq)加入到溶有2,2'–(硫代羰基(硫))二乙酸(976mg,4.32mmol,1.2eq)的异丙醇(4mL)中,然后再往体系中滴入Et3N(1mL,7.2mmol,2eq)。将反应体系加热至82°摄氏度,搅拌1h。TLC监测反应结束后,浓缩干后,经硅胶柱分离得到产物5a1(638mg,2.91mmol),白色固体,熔点:55℃,收率81%。
1H NMR(400MHz,CDCl3)δ4.69(s,2H),4.20(q,J=7.5Hz,2H),4.05(s,2H),1.26(t,J=7.5Hz,3H).
实施例8:合成2-(4-氧代-2-硫代噻唑烷-3-基)乙酸叔丁酯5a2
甘氨酸叔丁酯盐酸盐(500mg,3mmol,1eq)和2,2'–(硫代羰基(硫))二乙酸(813mg,3.6mmol,,1.2eq),参照实施例7操作过程,分离得产物5a2(504mg),白色固体,熔点:57℃,收率68%。
1H NMR(400MHz,CDCl3)δ4.59(s,2H),4.04(s,2H),1.44(s,9H).
实施例9:合成2-(4-氧代-2-硫代噻唑烷-3-基)丙酸乙酯5b1
3-氨基丙酸乙酯盐酸盐(500mg,3.27mmol,1eq)和2,2'–(硫代羰基(硫))二乙酸(886mg,3.92mmol,1.2eq),参照实施例7操作过程,分离得产物5b1(708mg),白色固体,熔点:83℃,收率93%。
1H NMR(400MHz,CDCl3)δ4.26(t,J=7.5Hz,2H),4.11(q,J=7.2Hz,2H),3.97(s,2H),2.65(t,J=7.5Hz,2H),1.24(t,J=7.5Hz,3H).
实施例10:合成2-(4-氧代-2-硫代噻唑烷-3-基)丙酸叔丁酯5b2
3-氨基丙酸叔丁酯盐酸盐(500mg,2.76mmol,1eq)和2,2'–(硫代羰基(硫))二乙酸(749mg,3.15mmol,1.2eq),参照实施例7操作过程,分离得产物5b2(467mg),白色固体,熔点:52℃,收率62%。
1H NMR(400MHz,CDCl3)δ4.22(t,J=7.5Hz,2H),3.95(s,2H),2.58(t,J=7.5Hz,2H),1.22(s,9H).
实施例11:合成(E)-2-(5-((10-甲基-10H-吩噻嗪-3-基)亚甲基)-4-氧代-2-硫代四氢噻吩-3-基)乙酸乙酯6a1
称取化合物2a(80mg,0.33mmol,1eq)和5a1(80mg,0.36mmol,1.1eq)分别溶于DCM(1.5mL)中混合均匀。在反应体系中滴加哌啶(98 L,3eq),室温下搅拌3h,TLC监测反应结束后,用10%的HCl调节pH至7。有机相用饱和食盐水清洗,硫酸镁干燥后再浓缩干,经硅胶柱分离得到产物6a1(100mg),红色固体,熔点:162℃,收率68.4%。
1H NMR(400MHz,CDCl3)δ7.62(s,1H),7.3(dd,J=8.5,2.0Hz,1H),7.22(d,J=2.0Hz,1H),7.17(td,J=7.6,1.4Hz,1H),7.12(dd,J=7.6,1.2Hz,1H),6.97(t,J=7.6Hz,1H),6.83(d,J=8.4Hz,1H),6.82(d,J=8.2Hz,1H),4.8(s,2H),4.22(q,J=7.0Hz,2H),3.40(s,3H),1.27(t,J=7.2Hz,3H);ESI-MS m/z:443.1[M+H]+。
实施例12:合成(E)-2-(5-((10-甲基-10H-吩噻嗪-3-基)亚甲基)-4-氧代-2-硫代四氢噻吩-3-基)乙酸叔丁酯6a2
化合物2a(229mg,0.95mmol),参照实施例11操作过程,分离得产物6a2(350mg),红色固体,熔点:132℃,收率78.3%。
1H NMR(400MHz,CDCl3)δ7.61(s,1H),7.3(dd,J=8.0,2.0Hz,1H),7.21(d,J=2.0Hz,1H),7.17(td,J=7.5,1.5Hz,1H),7.12(dd,J=8.0,1.5Hz,1H),6.96(t,J=7.5Hz,1H),6.83(d,J=8.0Hz,1H),6.82(d,J=8.0Hz,1H),4.73(s,2H),3.40(s,3H),1.44(s,9H);471.2[M+H]+。
实施例13:合成(E)-2-(5-((8-氯-10-甲基-10H-吩噻嗪-3-基)亚甲基)-4-氧代-2-硫代四氢噻吩-3-基)乙酸乙酯6b1
化合物2b(200mg,0.73mmol),参照实施例11操作过程,分离得产物6b1(270mg),暗红色固体,熔点:173℃,收率78%。
1H NMR(400MHz,CDCl3)δ7.61(s,1H),7.31(dd,J=8.5,2.0Hz,1H),7.2(d,J=2.0Hz,1H),7.01(d,J=8.5Hz,1H),6.94(dd,J=8.0,2.0Hz,1H),6.84(d,J=8.0Hz,1H),6.89(d,J=2.0Hz,1H),4.83(s,2H),4.22(q,J=7.0Hz,2H),3.38(s,3H),1.27(t,J=7.0Hz,3H);ESI-MS m/z:477.1[M+H]+。
实施例14:合成(E)-2-(5-((8-氯-10-甲基-10H-吩噻嗪-3-基)亚甲基)-4-氧代-2-硫代四氢噻吩-3-基)乙酸叔丁酯6b2
化合物2b(180mg,0.65mmol),参照实施例11操作过程,分离得产物6b2(270mg),暗红色固体,熔点:208℃,收率83%。
1H NMR(400MHz,CDCl3)δ7.60(s,1H),7.3(dd,J=8.5,2.0Hz,1H),7.2(d,J=2.0Hz,1H),7.02(d,J=8.0Hz,1H),6.94(dd,J=8.5,2.0Hz,1H),6.84(d,J=8.0Hz,1H),6.79(d,J=2.0Hz,1H),4.73(s,2H),3.38(s,3H),1.23(s,9H);ESI-MS m/z:505.1[M+H]+。
实施例15:合成(E)-2-(5-((8-(二甲基氨基)-10-甲基-10H-吩噻嗪-3-基)亚甲基)-4-氧代-2-硫代四氢噻吩-3-基)乙酸叔丁酯6c2
化合物2c(200mg,0.70mmol),参照实施例11操作过程,分离得产物6b2(249mg),红色固体,熔点:155℃,收率69%。
1H NMR(400MHz,CDCl3)δ7.77(s,1H),7.15(t,J=8.0Hz,1H),7.13-7.09(m,2H),6.94(t,J=7.5Hz,1H),6.82(d,J=8.0Hz,1H),6.45(s,1H),4.72(s,2H),3.40(s,3H),2.71(s,6H),1.44(s,9H);ESI-MS m/z:514.2[M+H]+。
实施例16:合成(E)-2-(5-((10-甲基-10H-吩噻嗪-3-基)亚甲基)-4-氧代-2-硫代四氢噻吩-3-基)乙酸7a
称取化合物6a2(200mg,0.43mmol)溶于3mL DCM中,滴加600 L三氟乙酸,在室温下搅拌2h,反应体系中有红色固体析出。TLC监测反应结束后,浓缩干燥后采用重结晶的方法得到纯净的化合物7a(161mg),红色固体,熔点:253℃,收率是92%。
1H NMR(400MHz,(CD3)2CO)δ7.71(s,1H),7.52(dd,J=8.5,2Hz,1H),7.4(d,J=2Hz,1H),7.25(td,J=7.5,1.0Hz,1H),7.17(dd,J=7.5,1.0Hz,1H),7.13(d,J=8.5Hz,1H),7.05-7.00(m,2H),4.87(s,2H),3.48(s,3H);ESI-MS m/z:415.1[M+H]+。
实施例17:合成(E)-2-(5-((8-氯-10-甲基-10H-吩噻嗪-3-基)亚甲基)-4-氧代-2-硫代四氢噻吩-3-基)乙酸7b
化合物6b2(150mg,0.31mmol,1eq),参照实施例16操作过程,分离得产物7b(132mg),红色固体,熔点:242℃,收率是94%。
1H NMR(400MHz,CDCl3)δ7.97(s,1H),7.71(dd,J=8.5,2.0Hz,1H),7.63(d,J=2.0Hz,1H),7.37(d,J=8.0Hz,1H),7.32(d,J=8.0Hz,1H),7.26-7.24(m,2H),4.89(s,2H),3.56(s,3H);ESI-MS m/z:449.1[M+H]+。
实施例18:合成(E)-2-(5-((8-(二甲基氨基)-10-甲基-10H-吩噻嗪-3-基)亚甲基)-4-氧代-2-硫代四氢噻吩-3-基)乙酸7c
化合物6c(195mg,0.38mmol),参照实施例16操作过程,分离得产物7c(159mg),红色固体,熔点:289℃,收率是92%。
1H NMR(400MHz,DMSO)δ7.76(s,1H),7.31(s,1H),7.24(td,J=8.0,1.5Hz,1H),7.17(dd,J=8.0,1.0Hz,1H),7.02-7.0(m,2H),6.67(s,1H),4.70(s,2H),3.41(s,3H),2.70(s,6H);ESI-MS m/z:458.1[M+H]+。
实施例19:合成(E)-N,N-二甲基-2-(5-((10-甲基-10H-吩噻嗪-3-基)亚甲基)-4-氧代-2-硫代四氢噻吩-3-基)乙酰胺8a
将化合物7a(500mg,1.2mmol,1eq),二甲胺(2mol/L,120 L,2eq),BOP(1g,2.26mmol,1.9eq)和N,N-二异丙基乙胺(387mg,3mmol,2.5eq)加入到有二氯甲烷(3mL)的25mL的圆底烧瓶中,反应3h。TLC监测反应结束后,加入DCM(10mL)和水,有机相干燥浓缩干后,经硅胶柱分离提纯得到化合物8a(480mg),暗红色固体,熔点:217℃,收率90.5%。
1H NMR(400MHz,CDCl3)δ7.61(s,1H),7.3(dd,J=8.5,2.0Hz,1H),7.21(d,J=2.0Hz,1H),7.17(td,J=7.5,1.5Hz,1H),7.12(dd,J=7.5,1.5Hz,1H),6.96(td,J=7.5,1.0Hz 1H),6.85-6.80(m,2H),4.91(s,2H),3.40(s,3H),3.11(s,3H),2.97(s,3H);ESI-MSm/z:442.1[M+H]+。
实施例20:合成(E)-2-(5-((10-甲基-10H-吩噻嗪-3-基)亚甲基)-4-氧代-2-硫代四氢噻吩-3-基)丙酸乙酯9a1
化合物2a(150mg,0.62mmol,1eq)和2-(4-氧代-2-硫代噻唑烷-3-基)丙酸乙酯(160mg,0.68mmol,1.1eq),参照实施例11操作过程,分离得产物9a1(246mg),红色固体,熔点:177℃,收率87%。
1H NMR(400MHz,CDCl3)δ7.58(s,1H),7.28(dd,J=8.5,2.0Hz,1H),7.2(d,J=2.0Hz,1H),7.17(td,J=7.5,1.5Hz,1H),7.12(dd,J=7.5,1.5Hz,1H),6.96(t,J=7.5Hz,1H),6.84-6.80(m,2H),4.4(t,J=7Hz,2H),4.13(q,J=7.0Hz,1H),3.40(s,3H),2.73(t,J=7.5Hz,2H),1.24(t,J=7.5Hz,3H);ESI-MS m/z:457.1[M+H]+。
实施例21:合成(E)-2-(5-((10-甲基-10H-吩噻嗪-3-基)亚甲基)-4-氧代-2-硫代四氢噻吩-3-基)丙酸叔丁酯9a2
化合物2a(100mg,0.42mmol,1eq)和2-(4-氧代-2-硫代噻唑烷-3-基)丙酸叔丁酯(119mg,0.46mmol,1.1eq),参照实施例11操作过程,分离得产物9a2(160mg),红色固体,熔点:182℃,收率80%。
1H NMR(400MHz,CDCl3)δ7.57(s,1H),7.29(dd,J=8.5,2.0Hz,1H),7.2(d,J=2.0Hz,1H),7.17(td,J=7.5,1.5Hz,1H),7.12(dd,J=7.5,1.5Hz,1H),6.97(t,J=7.5Hz,1H),6.84-6.80(m,2H),4.36(t,J=7Hz,2H),3.39(s,3H),2.65(t,J=7.5Hz,2H),1.42(s,9H);ESI-MS m/z:485.1[M+H]+。
实施例22:合成(E)-2-(5-((10-甲基-10H-吩噻嗪-3-基)亚甲基)-4-氧代-2-硫代四氢噻吩-3-基)丙酸10a
化合物9a2(200mg,0.43mmol),参照实施例16操作过程,分离得产物10a(161mg),红色固体,熔点:250℃,收率是92%。
1H NMR(400MHz,DMSO)δ12.51(bs,1H),7.72(s,1H),7.48(dd,J=8.5,2.0Hz,1H),7.42(d,J=2.0Hz,1H),7.25(td,J=7.5,1.5Hz,1H),7.19(dd,J=7.5,1.5Hz,1H),7.11(d,J=8.5Hz,1H),7.05-6.99(m,2H),4.22(t,J=7.0Hz,2H),3.38(s,3H),2.62(t,J=7.5Hz,2H);ESI-MS m/z:429.1[M+H]+。
实施例23:合成2-(5-(10-甲基-10H-吩噻嗪-3-基)亚烯丙基)-4-氧代-2-硫代四氢噻吩-3-基)乙酸乙酯11a1
化合物3a(210mg,0.78mmol,1eq)和2-(4-氧代-2-硫代噻唑烷-3-基)乙酸乙酯(188mg,0.86mmol,1.1eq),参照实施例11操作过程,分离得产物11a1(230mg),红色固体,熔点:100℃,收率64%。
1H NMR(400MHz,CDCl3)δ7.44(d,J=11.0Hz,1H),7.30-7.27(m,2H),7.17(td,J=7.5,1.5Hz,1H),7.12(dd,J=7.5,1.5Hz,1H),6.98-6.92(m,2H),6.82(d,J=8.0Hz,1H),6.77(d,J=8.0Hz,1H),6.59(dd,J=11.0,11.0Hz,1H),4.80(s,2H),4.21(q,J=7.0Hz,2H),3.39(s,3H),1.26(t,J=7.1Hz,3H);ESI-MS m/z:469.1[M+H]+。
实施例24:合成2-(5-(10-甲基-10H-吩噻嗪-3-基)亚烯丙基)-4-氧代-2-硫代四氢噻吩-3-基)乙酸叔丁酯11a2
化合物3a(300mg,1.12mmol,1eq)和2-(4-氧代-2-硫代噻唑烷-3-基)乙酸叔丁酯(304mg,1.23mmol,1.1eq),参照实施例11操作过程,分离得产物11a2(357mg),红色固体,熔点:202℃,收率68%。
1H NMR(400MHz,CDCl3)δ7.43(d,J=12.0Hz,1H),7.32-7.26(m,2H),7.17(td,J=7.5,1.5Hz,1H),7.12(dd,J=7.5,1.5Hz,1H),6.99-6.91(m,2H),6.82(d,J=8.0Hz,1H),6.76(d,J=8.0Hz,1H),6.58(dd,J=11.0,11.0Hz,1H),4.70(s,2H),4.38(s,3H),1.44(s,9H);ESI-MS m/z:497.2[M+H]+。
实施例25:合成2-(5-(8-氯-10-甲基-10H-吩噻嗪-3-基)亚烯丙基)-4-氧代-2-硫代四氢噻吩-3-基)乙酸叔丁酯11b2
化合物3b(270mg,0.9mmol,1eq)和2-(4-氧代-2-硫代噻唑烷-3-基)乙酸叔丁酯(250mg,0.99mmol,1.1eq),参照实施例11操作过程,分离得产物11b2(250mg),红色固体,熔点:202℃,收率52.6%。
1H NMR(400MHz,CDCl3)δ7.42(d,J=12.0Hz,1H),7.29(dd,J=7.5,1.5Hz,1H),7.26(d,J=1.5Hz,1H),7.01(d,J=12.0Hz,1H),6.92(dd,J=7.5,1.5Hz,1H),6.77(d,J=2.0Hz,1H),6.61(m,2H),6.57(dd,J=11.0,11.0Hz,1H),4.74(s,2H),3.36(s,3H),1.44(s,9H);ESI-MS m/z:531.1[M+H]+。
实施例26:合成2-(5-(10-甲基-10H-吩噻嗪-3-基)亚烯丙基)-4-氧代-2-硫代四氢噻吩-3-基)乙酸12a
化合物11a2(198mg,0.4mmol),参照实施例16操作过程,分离得产物12a(168mg),红色固体,熔点:246℃,收率是95%。
1H NMR(400MHz,DMSO)δ7.62(d,J=3.5Hz,1H),7.56(d,J=8.0Hz,1H),7.51(dd,J=8.0,3.5Hz,1H),7.32(d,J=15.0Hz,1H),7.23(t,J=7.0Hz,1H),7.18(dd,J=8.0,3.5Hz,1H),7.07(dd,J=15.0,15.0Hz,1H),7.05-6.95(m,3H),4.69(s,2H),3.35(s,3H);ESI-MS m/z:441.1[M+H]+。
实施例27:合成2-(5-(8-氯-10-甲基-10H-吩噻嗪-3-基)亚烯丙基)-4-氧代-2-硫代四氢噻吩-3-基)乙酸12b
化合物11b2(150mg,0.28mmol),参照实施例16操作过程,分离得产物12b(121mg),红色固体,熔点:246℃,收率是90%。
1H NMR(400MHz,(CD3)2CO)δ7.58-7.51(m,3H),7.30(d,J=15.0,1H),7.26(d,J=8.0Hz,1H),7.15(d,J=8.0Hz,1H),7.08-6.98(m,4H),4.84(s,2H),3.86(s,3H);ESI-MS m/z:475.1[M+H]+。
实施例28:合成2-(5-(10-甲基-10H-吩噻嗪-3-基)亚烯丙基)-4-氧代-2-硫代四氢噻吩-3-基)丙酸叔丁酯13a2
化合物3a(100mg,0.37mmol,1eq)和2-(4-氧代-2-硫代噻唑烷-3-基)丙酸叔丁酯(108mg,0.41mmol,1.1eq)参照实施例11操作过程,分离得产物13a2(118mg),红色固体,熔点:202℃,收率是62%。
1H NMR(400MHz,CDCl3)δ7.42(d,J=12.0Hz,1H),7.32-7.28(m,2H),7.19(td,J=7.5,1.5Hz,1H),7.14(dd,J=7.5,1.5Hz,1H),7.00-6.92(m,2H),6.84(d,J=8.0Hz,1H),6.78(d,J=8.0Hz,1H),6.59(dd,J=13.0,13.0Hz,1H),4.35(t,J=7.5Hz,1H),3.40(s,2H),2.66(t,J=7.5Hz,1H),1.44(s,9H);ESI-MS m/z:511.2[M+H]+。
实施例29:合成2-(5-(10-甲基-10H-吩噻嗪-3-基)亚烯丙基)-4-氧代-2-硫代四氢噻吩-3-基))丙酸14a
化合物13a2(100mg,0.2mmol)参照实施例16操作过程,分离得产物14a(77.5mg),红色固体,熔点:267℃,收率是87%。
1H NMR(400MHz,DMSO)δ13.4(s,1H),7.62(d,J=3.5Hz,1H),7.52-7.46(m,2H),7.29(d,J=15.0Hz,1H),7.23(t,J=8.0Hz,1H),7.18(dd,J=8.0,3.5Hz,1H),7.06-6.95(m,4H),4.19(t,J=8.0Hz,2H),3.23(s,3H)2.60(t,J=8.0Hz,2H).ESI-MS m/z:455.1[M+H]+。
实施例30:合成2-(5-(10-甲基-10H-吩噻嗪-3-基)戊-2,4-二烯-1-亚基)-4-氧代-2-硫代四氢噻吩-3-基)乙酸乙酯15a1
化合物4a(210mg,0.72mmol,1eq)和2-(4-氧代-2-硫代噻唑烷-3-基)乙酸乙酯(172mg,0.79mmol,1.1eq),参照实施例11操作过程,分离得产物15a1(226mg),红色固体,熔点:282℃,收率64%。
1H NMR(400MHz,CDCl3)δ7.38(d,J=12.0Hz,1H),7.22(m,2H),7.16(td,J=7.5,1.5Hz,1H),7.12(dd,J=7.5,1.5Hz,1H),6.94(td,J=7.5,1.5Hz,1H),6.90(d,J=12.0Hz,1H),6.86-6.71(m,4H),6.27(t,J=12.0Hz,1H),4.79(s,2H),4.21(q,J=7.0Hz,2H),3.38(s,3H),1.26(t,J=7.1Hz,3H);ESI-MS m/z:495.1[M+H]+。
实施例31:合成2-(5-(10-甲基-10H-吩噻嗪-3-基)戊-2,4-二烯-1-亚基)-4-氧代-2-硫代四氢噻吩-3-基)乙酸叔丁酯15a2
化合物4a(210mg,0.72mmol,1eq)和2-(4-氧代-2-硫代噻唑烷-3-基)乙酸乙酯(172mg,0.79mmol,1.1eq),参照实施例11操作过程,分离得产物15a2(226mg),红色固体,熔点:282℃,收率64%。
1H NMR(400MHz,CDCl3)δ7.39(d,J=12.0Hz,1H),7.26-7.23(m,2H),7.18(td,J=7.5,1.5Hz,1H),7.14(dd,J=7.5,1.5Hz,1H),6.95(td,J=7.5,1.5Hz,1H),6.92-6.71(m,5H),6.28(t,J=12.0Hz,1H),4.71(s,2H),3.39(s,3H),1.46(s,9H);ESI-MS m/z:523.2[M+H]+。
实施例32:合成2-(5-(10-甲基-10H-吩噻嗪-3-基)戊-2,4-二烯-1-亚基)-4-氧代-2-硫代四氢噻吩-3-基)乙酸16
化合物15a2(100mg,0.19mmol)参照实施例16操作过程,分离得产物16(75mg),红色固体,熔点:190℃,收率84%。
1H NMR(400MHz,DMSO)δ7.55(d,J=12.0Hz,1H),7.43(dd,J=8.0,1.5Hz,1H),7.40(d,J=1.5Hz,1H),7.26-7.16(m,3H),7.12(d,J=12.0Hz,1H),7.00-6.95(m,3H),6.91(d,J=12.0Hz,1H),6.51(t,J=12Hz,1H),4.63(s,2H),3.33(s,3H).ESI-MS m/z:467.1[M+H]+。
实施例33:合成3–(5-(10-甲基-10H-吩噻嗪-3-基)戊-2,4-二烯-1-亚基)-2,4-硫代噻唑烷-3-基)丙酸叔丁酯17a2
化合物4a(210mg,0.72mmol,1eq)和2-(4-氧代-2-硫代噻唑烷-3-基)丙酸叔丁酯(208mg,0.79mmol,1.1eq),参照实施例11操作过程,分离得产物17a2(234mg),红色固体,熔点:174℃,收率61%。
1H NMR(400MHz,CDCl3)δ7.34(d,J=12.0Hz,1H),7.25-7.21(m,2H),7.18(td,J=7.5,1.5Hz,1H),7.13(dd,J=7.5,1.5Hz,1H),6.95(td,J=7.5,1.5Hz,1H),6.90-6.70(m,5H),6.24(t,J=12.0Hz,1H),4.33(t,J=12.0Hz,2H),3.37(s,3H),2.65(t,J=12.0Hz,2H),1.44(s,9H);ESI-MS m/z:537.2[M+H]+。
实施例34:合成3–(5-(10-甲基-10H-吩噻嗪-3-基)戊-2,4-二烯-1-亚基)-2,4-硫代噻唑烷-3-基)丙酸18
化合物17a2(100mg,0.19mmol)参照实施例16操作过程,分离得产物18(75mg),红色固体,熔点:247℃,收率84%。
1H NMR(400MHz,DMSO)δ12.5(s,1H),7.49(d,J=12.0Hz,1H),7.42(dd,J=8.0,1.5Hz,1H),7.39(d,J=1.5Hz,1H),7.23(td,J=8.0,1.5Hz,1H),7.19(dd,J=8.0,1.5Hz,1H),7.16(d,J=1.5Hz,1H),7.11(d,J=12.0Hz,1H),7.00-6.94(m,3H),6.89(d,J=12.0Hz,1H),6.48(t,J=12Hz,1H),4.18(t,J=8.0Hz,2H),3.32(s,3H),2.59(t,J=8.0Hz,2H).ESI-MS m/z:481.1[M+H]+。
下面是吩噻嗪衍生物的实验测试结果。
1)吩噻嗪衍生物的吸收和发射(见表1):
吸收光谱和发射波长是用多模式分光光度计(多功能酶标仪spectramaxParadigm,旧金山,加利福尼亚,美国)测试。
2)结合试验(见表2):
采用Aβ(1-42)聚集体固定浓度为1μM和不同浓度的荧光化合物结合。荧光信号检测是根据各自化合物的激发/发射光谱。Kd值采用Grafpad Prism软件计算确定。
3)β-淀粉样蛋白的自聚集抑制活性测试方法(见表2):
β-淀粉样蛋白(Aβ1-42)冻干粉溶解于六氟异丙醇,室温静置16个小时进行解聚,再在室温下用氮气流吹除六氟异丙醇,得解聚的Aβ1-42用DMSO溶解配制成浓度为200μM溶液,用荧光法测定化合物的Aβ自聚集抑制活性。反应总容量为10μL,内含样品的DMSO溶液5μL(浓度为200μM),解聚的Aβ1-42DMSO溶液5μL(浓度为200μM),在37℃保温72h后加入硫黄素T的磷酸二氢钾缓冲液(PH=7.4)溶液40μL(浓度为200μM),在paradigm微孔板检测仪上读取荧光值,激发波长为485nm,发射波长下为435nm。所有样品均平行测三次,以未加化合物的测定组吸光度作为100%,测定的化合物组荧光值与未加化合物组相比较,降低的百分率即为在20μM浓度下Aβ自聚集抑制率。
具体得到的测试结果如下:
如表1所示,所有化合物最大吸收和荧光发射光谱值分别在470~510nm和640~700nm之间。大部分的化合物的发射光谱值>650nm。
表1:吩噻嗪衍生物吸收和荧光发射波长
如表2所示的化合物于Aβ(1-42)自聚体的结合能力测试结果来看,除了化合物7b之外,这类化合物具有很强的于Aβ自聚体结合能力,特别是化合物6a1,其Kd值仅为7.5。另外,在体外化合物与β-淀粉样蛋白的自聚集抑制活性测试中显示,除化合物12b之外,剩下的所有化合物对Aβ1-42的自聚集具有较好的抑制作用,它们的抑制作用都比对照物姜黄素要强,特别是化合物12a,达到了84.9%抑制强度,而同等条件下,姜黄素的抑制强度仅为41%。因此,这类化合物也具有治疗抗阿茨海默症的潜力。
表2:吩噻嗪衍生与Aβ自聚集体的结合常数和抑制率
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (5)
1.一种吩噻嗪衍生物,其特征在于:具有如下所示的结构式:
2.根据权利要求1所述的吩噻嗪衍生物制备的盐,其特征在于:包括由权利要求1中的吩噻嗪衍生物在醇溶液中与盐酸、醋酸、三氟乙酸制备相应的盐酸盐、醋酸盐、三氟乙酸盐。
3.权利要求1所述的吩噻嗪衍生物的制备方法,其特征在于:包括如下步骤:
(1)中间体醛化合物2,3的制备:吩噻嗪甲基化之后,经维尔斯迈尔-哈克反应引入醛基,得到化合物2,再经磷叶立德反应引入一个烯烃键,得到化合物3;
(2)中间体5的制备:甘氨酸乙酯与2,2'–(硫代羰基(硫))二乙酸进行缩合反应,得到中间体5;
(3)化合物6a1的制备:10-甲基-10H-吩噻嗪-3-甲醛化合物2与中间体5进行Knoevenagel缩合反应,得到化合物6a1;
(4)化合物11a1的制备:参照步骤(3)中有关的反应,(E)-3-(10-甲基-10H-吩噻嗪-3-基)丙烯醛化合物3与中间体5进行Knoevenagel缩合反应,得到化合物11a1。
4.权利要求1所述的吩噻嗪衍生物或权利要求2所述的盐的应用,其特征在于:应用于制备阿尔茨海默氏病淀粉样蛋白β斑块成像的近红外荧光分子探针。
5.权利要求1所述的吩噻嗪衍生物或权利要求2所述的盐的应用,其特征在于:应用制备治疗阿尔茨海默氏病的药物。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610380172.5A CN106045986B (zh) | 2016-05-31 | 2016-05-31 | 一种新型吩噻嗪衍生物及其制备方法与应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610380172.5A CN106045986B (zh) | 2016-05-31 | 2016-05-31 | 一种新型吩噻嗪衍生物及其制备方法与应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN106045986A CN106045986A (zh) | 2016-10-26 |
CN106045986B true CN106045986B (zh) | 2019-12-06 |
Family
ID=57173203
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610380172.5A Expired - Fee Related CN106045986B (zh) | 2016-05-31 | 2016-05-31 | 一种新型吩噻嗪衍生物及其制备方法与应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN106045986B (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107325809B (zh) * | 2017-05-17 | 2019-10-18 | 华南理工大学 | 一种与Aβ斑块具有亲和力的荧光化合物及制备与应用 |
CN108675280B (zh) * | 2018-06-21 | 2021-09-24 | 大连理工大学 | 吩噻嗪衍生物荧光碳点及其制备方法和应用 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2543666A1 (en) * | 2010-03-01 | 2013-01-09 | Nihon Medi-Physics Co., Ltd. | Radioactive iodine labeled organic compound or salt thereof |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1192143A1 (en) * | 1999-06-10 | 2002-04-03 | Warner-Lambert Company | Rhodanine derivatives for use in a method of inhibiting amyloid protein aggregation and imaging amyloid deposits |
-
2016
- 2016-05-31 CN CN201610380172.5A patent/CN106045986B/zh not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2543666A1 (en) * | 2010-03-01 | 2013-01-09 | Nihon Medi-Physics Co., Ltd. | Radioactive iodine labeled organic compound or salt thereof |
Non-Patent Citations (1)
Title |
---|
Fluorescent rhodanine-3-acetic acids visualize neurofibrillary tangles in Alzheimer’s disease brains;Upendra Rao Anumala et al.;《Bioorganic & Medicinal Chemistry》;20130627;第21卷;第5139-5144页;第5140页右栏第3段,第5141-5142页表1和Scheme 1 * |
Also Published As
Publication number | Publication date |
---|---|
CN106045986A (zh) | 2016-10-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN112779001B (zh) | 一种近红外粘度荧光探针的制备及其应用 | |
CN108191789B (zh) | 一种吩噻嗪衍生物、其制备方法和应用 | |
CN110746410B (zh) | 一种亮氨酸氨肽酶和单胺氧化酶激活的近红外荧光探针、合成方法及生物应用 | |
CN109970751B (zh) | 一种双位点、高灵敏pH荧光探针及其合成与应用 | |
JP4373608B2 (ja) | 一重項酸素測定用試薬 | |
CN103030605A (zh) | 一种非布索坦原料的制备方法和检测方法 | |
CN106045986B (zh) | 一种新型吩噻嗪衍生物及其制备方法与应用 | |
CN113024463B (zh) | 一种1,8-萘酰亚胺类硫化氢荧光分子探针的制备和应用 | |
EP2778161B1 (en) | Two-photon fluorescent probe using naphthalene as matrix and preparation method and use thereof | |
KR101171919B1 (ko) | 티올 선택성을 갖는 플루오레세인 유도체를 포함하는 형광 센서 및 이를 이용한 티올 검출방법 | |
US5639906A (en) | Fluorescent and NMR sensitive pH indicators | |
CN112794847B (zh) | 一种顺序检测水合肼和亚硫酸氢根的新型荧光探针及其合成及应用 | |
CN105295896B (zh) | 一种特异性标记的辣椒素荧光探针及其合成方法和应用 | |
CN110590664A (zh) | 一种荧光探针的制备方法及该荧光探针的应用 | |
CN111233913A (zh) | 一种制备区分和识别对映异构体的含氟试剂 | |
CN115746036A (zh) | 一种靶向识别Aβ纤维的荧光探针SN-BODIPY化合物及其制备方法 | |
Capon et al. | (+)-Echinobetaine B: isolation, structure elucidation, synthesis and preliminary SAR studies on a new nematocidal betaine from a southern Australian marine sponge, Echinodictyum sp. | |
CN102702074B (zh) | 一种以咔唑为荧光团的磺酰氯类化合物的制备方法 | |
CN110551498A (zh) | 一种检测Hg2+的香豆素类荧光探针的制备及应用 | |
EP0381628B1 (en) | Glycocyamidine derivatives | |
WO2007131054A2 (en) | Chromoionophore and method of determining sodium ions | |
CN109988561A (zh) | 咪唑并[1,2-a]吡啶类比率型pH荧光探针及其制备方法和应用 | |
CN113185559B (zh) | 用于检测肿瘤的糖基杯芳烃荧光探针 | |
CN115925767B (zh) | 用于结肠肿瘤早期检测β-半乳糖苷酶的红光发射探针及其制备方法 | |
CN114957293B (zh) | 用于特异性识别胰岛素的基于鸟嘌呤的花菁探针及其制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20191206 Termination date: 20200531 |
|
CF01 | Termination of patent right due to non-payment of annual fee |